Developing & Testing 2nd Generation Oncology Focused Potent & Bioselective PermaLink-derived ADCs

At their simplest Antibody Drug Conjugates (ADCs) comprise a linker that joins an antibody to a cell toxic warhead. The rapidly expanding ADC pipeline focuses on oncology & currently has >55 compounds in trials. Two ADCs have been approved (FDA) - ADCETRIS which uses a protease-sensitive linker & Kadcyla with a non-cleavable linker. There are only a few chemical strategies available that join the linker-warhead motif to the antibody (bioconjugation), however one of the most important (as used here) exploits the natural & reactive amino acid cysteine.
We propose a new industry-academic collaboration between Glythera a Newcastle-based SME & next generation ADC specialist and UEA. Exploiting our complementary skills we will co-develop a suite of ADCs using a bioconjugation reaction between Glythera's proprietary heterocycle-based linker technology (PermaLink) & antibody-bound cysteine(s). Coupling highly potent toxin(s) we will establish innovative bioconjugation methods that will be optimised affording fully functioning drug-loaded ADCs. Dovetailing Glythera's biology/bioconjugation expertise with SPB's synthetic chemistry capability we will develop:
1. More reactive, novel heterocycles (PermaLinks) that react with one cysteine.
2. Using these PermaLinks to react them with 1 or 2, identical or different cytotoxic warheads. Introducing different warheads is important for combating multi-drug resistance, increasing potency & clinical efficacy.
Why is the linker important? It has a crucial role in ADC safety & efficacy. It has to be stable in plasma preventing premature warhead release (this increases off-target toxicity) but, critically, upon internalisation it has to release the warhead at the desired location (on target toxicity). Furthermore if the linker-warhead motif is too greasy its reaction with the antibody is problematic. Furthermore greasy ADCs are less soluble this results in further complications i.e.hepatotoxicity, immunogenicity & multi-drug resistance. Combating this we will generate more hydrophilic PEGylated ADCs using PermaLink technology that has excellent biostability when compared to the current Gold Standard (maleimide). However, since its development in 2007 no studies on alternative, more reactive, PermaLinks have been undertaken that incorporate different functional groups for linker-warhead assembly eg azide /alkyne. This PhD will probe these aspects generating new PermaLinkers which will seek to:
1 Increase ADC hydrophilicity & homogeneity
2 Effect high & consistently reproducible DARs
3 Improve ADC PK profiles
4 Maintain PermaLink biostability
This PhD will have 6 Key Objectives:
1 Probe PermaLink SAR determining what can/cannot be changed to IMPROVE REACTIVITY & MAINTAIN BIOSTABILITY
2 Bioconjugate 2nd generation PermaLinkers to 'conventional' warheads & subsequently antibodies generating NOVEL ADCs. Purify & determine their DARs, test efficacy/cell killing assays
3 Develop NEW potent oncology targeting ADCs (non-conventional warhead) with EXCELLENT biostability properties & homogeneity
4 Develop NEW dual warhead PermaLinks & install 2 identical or 2 different cytotoxic payloads. Purify & determine their DARs, test efficacy/cell killing assays
5 File for NEW IP & or write up chemistry & biological results for HIGH IMPACT PUBLICATIONS
6 Submit a PhD
This PhD will:
1 Facilitate, strengthen, augment future grant applications between Glythera & UEA
2 Train a highly sought after PhD in state-of-the art synthesis & biotherapeutics
3 Aid our long term goal of enhancing clinical efficacy, patient safety & improve the success rate in the transformational & rapidly advancing field of ADCs
This multidisciplinary academic/industry research collaboration is an excellent opportunity to strategically align the synthesis & ADC communities, furthermore the development of new ADCs is perfectly aligned with MRC research priorities of developing modalities for treating human disease.